ABSTRACT Basal cell carcinoma (BCC) is driven by constitutive activation of the Hedgehog (Hh) signaling pathway, most commonly through loss-of-function mutations in PTCH1. Our previous studies in mice have shown that upon deletion of Ptch1, microscopic BCC-like tumors preferentially arise from hair follicle stem cells. While our current BCC mouse model mimics the early features and genetics of this disease, our preliminary data also suggest that Ptch1 inactivation may not be sufficient for full progression to macroscopic tumors. Recent exome sequencing studies have revealed that BCCs harbor the highest mutational burden of all cancers and therefore, this proposal seeks to test whether recurrent mutations seen in human BCC collaborate with Hh signaling to drive BCC tumorigenesis. Indeed, previous studies have shown that loss-of-function mutations in NOTCH1/2 and gain-of- function mutations in MYCN are commonly detected in BCC. Here, we will examine whether loss of Notch1 and/or gain of MYCN collaborates with Hh signaling to drive the efficient formation of full-blown macroscopic BCC-like tumors. Overall, this proposal will determine whether these genetics events modulate stage-specific tumor progression and may open up novel therapeutic targeting strategies.